Site-selective and metal-free C–H phosphonation of arenes via photoactivation of thianthrenium salts

Aryl phosphonates are prevalent moieties in medicinal chemistry and agrochemicals. Their chemical synthesis normally relies on the use of precious metals, harsh conditions or aryl halides as substrates. Herein, we describe a sustainable light-promoted and site-selective C–H phosphonation of arenes via thianthrenation and the formation of an electron donor–acceptor complex (EDA) as key steps. The method tolerates a wide range of functional groups including biomolecules. The use of sunlight also promotes this transformation and our mechanistic investigations support a radical chain mechanism.


Reaction Workflow
All photoinduced reactions were done using a Kessil PR160-purple LED lamp (30 W High Luminous DEX 2100 LED, λmax = 390 nm). The LED was placed 4 cm away from the reaction vial within a ventilated fume hood and using a fan to maintain the temperature approximately at 25ºC. Figure S1. Reaction setup for the photoinduced phosphonation of arenes

General Procedure for the Photochemical Synthesis of Aryl Phosphonates
To a flame-dried 8 mL vial equipped with a magnetic stir bar, TT salt 1 (0.5 mmol, 1.0 equiv) and KHCO3 (50 mg, 0.5 mmol, 1.0 equiv) were added, and the vial was subjected to 3 cycles of vacuum/argon degassing.
Subsequently, 5 mL of dry MeCN were added under inert atmosphere. Subsequently, the corresponding phosphite was added via syringe (2.5 mmol, 5 equiv), and the solution was degassed with Argon for 30 seconds. The reaction mixture was irradiated for 30 minutes (unless otherwise noted) with a 390 nm Kessil PR160-purple LED as described in the "Workflow" section. The temperature of the reaction was maintained at approximately 25 °C via a fan. Upon completion, the solvent was removed under reduced pressure. The crude mixture was subjected to flash column purification using hexanes/EtOAc mixtures to yield the desired aryl phosphonate.

Sunlight-driven synthesis of 4
To an 8 mL Chemglass vial ( shown in Figure S2. The temperature in the room was 23ºC. Upon completion, the solvent was removed under high vacuum and the crude was subjected to purification by flash column chromatography (10 -60% EtOAc in hexanes). The title compound 4 was obtained as a tan oil (96 mg, 0.41 mmol, 82%). Figure S2. Setup for the sun-light driven synthesis of 4.
Then, the vial was purged with argon for 30 seconds and 2a was added in one portion via syringe (429 µL, 415 mg, 2.5 mmol, 5.0 equiv). The cap was covered with Parafilm and the reaction mixture was irradiated for 2.5 h with Abel LS-50 Light source as shown in Figure S3. The reaction vial was placed at 1 sun distance (intensity of simulator 100 mW/cm 2 ). The temperature in the room was 21ºC. Upon completion, the solvent was removed under high vacuum and the crude was subjected to purification by flash column chromatography (10 -60% EtOAc in hexanes). The title compound 22 was obtained as a tan oil (92 mg, 0.40 mmol, 79%). Figure S3. Setup for the synthesis of 22 using a solar simulator.

Large scale and Telescoped Synthesis of 18
4-Bromophenoxybenzene (1.25 g, 5.0 mmol, 1 equiv) was placed into a 50 mL round-bottomed flask equipped with a magnetic stir bar and dissolved with 8 mL of dry MeCN at 0ºC. Then, while stirring, thianthrene Soxide (1.16 g, 5.0 mmol, 1.0 equiv) was added, followed by HBF4·Et2O (0.75 mL, 0.9 g, 5.5 mmol, 1.1 equiv) S21 and trifluoroacetic anhydride (TFAA) (1.1 mL, 1.6 g, 7.5 mmol, 1.5 equiv). The ice bath was removed, and the reaction mixture was stirred for 3h. Then, the solution was diluted with 20 mL of CH2Cl2 and poured into a separatory funnel. The organic phase was washed with a satured solution of NaHCO3 (25x3 mL), and 10% NaBF4 aqueous solution (2 × 25 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The obtained crude was dissolved in 50 mL of dry MeCN and transferred into a 250 mL regular Schlenk flask. Then, KHCO3 (500 mg, 5.0 mmol, 1.0 equiv) was added, and the solvent purged with argon for 2 minutes. Afterwards, 2a was added in one portion via syringe (429 µL, 415 mg, 2.5 mmol, 5.0 equiv). The cap was covered with Parafilm and the reaction mixture was irradiated for 30 minutes with two Kessil PR160-blue LED lamps (30 W High Luminous DEX 2100 LED, λmax = 390 nm) as shown in Figure S4. The temperature of the reaction was maintained at approximately 25 °C via a fan. Upon completion, the solvent was removed under high vacuum and the crude was subjected to purification by flash column chromatography (10 -60% EtOAc in hexanes). The title compound 18 was obtained as a tan oil (1.61 g, 4.2 mmol, 84%).  The quantum yield of for our model photochemical reaction was determined using previously reported methods using equation 1: 6 Φ(reaction at 390 nm) = mol of formed product mol of photon flux · t · f (1)

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where Φ is the quantum yield of the reaction, t is the time of the reaction (s), f is the incident light absorbed by the EDA Complex at 390 nm and the photon flux is calculated by standard ferrioxalate actinometry.
The fraction of light, f, absorbed was determined according to equation 2: where A is the absorbance of the EDA Complex in MeCN at 390 nm. The wavelength of 390 nm was chosen based on the known absolute Φ(Fe +2 ) value 7 and is the wavelength we are using in our reaction. The absorbance of the EDA Complex was measured (0.1 M) in MeCN (2 mL). The absorbance (A) at 390 nm was determined to be >2, thus indicating the fraction of light absorbed is 0.99 according to equation 2.

Photon flux sample calculation
Standard ferrioxalate actinometry was used to determine the photon flux of the spectrophotometer using equations 3 and 4. For the ferrioxalate actinometer the production of iron(II) ions proceeds by the following reactions: The moles of Fe +2 formed are determined spectrophotometrically by development with 1,10-phenanthroline (phen) to form the red [Fe(phen)3] +2 moiety (λ = 510 nm). 8 The photon flux is defined as shown in equation 3: Where Φ is the quantum yield for the ferrioxalate actinometer (1.01 at λ = 438 nm), t is the time (s), and f ~1, and the mol of Fe +2 are calculated according to equation 4.
Where V is the total volume of the solution, ΔA is the difference in absorbance between irradiated and nonirradiated solutions, l is the path length (1.0 cm), ε is the molar absorptivity at 510 nm (11110 L mol -1 cm -1

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The following solutions were prepared in the dark (flasks were wrapped in aluminum foil) and stored in the dark at room temperature: − Ferrioxalate solution (0.15 M): Potassium ferrioxalate hydrate (0.656 g) was added to a flask wrapped in aluminum foil containing H2SO4 (10 mL, 0.05 M). The flask was stirred for complete dissolution of the green solid in complete darkness. It is noteworthy that the solution should not be exposed to any incident light.
The absorbance of the non-irradiated sample. The buffered solution of phen (350 µL) was added to a ferrioxalate solution (2.0 mL) in a vial that had been covered with aluminum foil and with the lights of the laboratory switched off. The vial was capped and allowed to rest for 1 h and then transferred to a cuvette. The absorbance of the non-irradiated sample was measured at 510 nm to be 1.45 (average of two determinations, light 1 and light 2, see Figure S6).
The absorbance of the irradiated sample. In a cuvette equipped with a stir bar was added the ferrioxalate solution (2.0 mL), and the stirred solution was irradiated for 30 s at λ = 390 nm with an excitation slit width = 10.0 nm. After irradiation, the buffered phen solution (350 µL) was added to the cuvette and allowed to rest for 1 h in the dark to allow the ferrous ions to coordinate completely to phen. The absorbance of the sample was measured at 510 nm to be 0.01.

Quantum yield determination
Therefore, the quantum yield of the reaction is determined to be: Φ(reaction at 390 nm) = mol of formed product mol of photon flux · t · f (1) ( ) = 1.5x10 −5 mol 2.85x10 −9 einstein s −1 · 45 s · 0.99 = 7.4. Cyclic Voltammetry of TT salt 1a We intentionally did not include the base in this experiment to detect the phosphonium intermediate E and thianthrene, as well as starting 1a, 2a, and maybe product. The 1 H NMR spectra confirmed our hypothesis and showed the formation of a new species which bears three OEt groups and thianthrene as main products ( Figure   S7). Additionally, a signal in 31 P NMR spectra appeared at a chemical shift of 31 ppm, suggesting a cationic phosphonium intermediate ( Figure S8). 9 In addition, both experiments showed that there was still unreacted 1a and traces of desired product. The formation of product was kind of expected because the reaction also works without the addition of any external base (see Table 1, entry 1 in the manuscript). Then, motivated by these observations a bidimensional 1 H/ 31 P HMBC experiment was done ( Figure S9). We confirmed that the new species containing three OEt groups attached to an aromatic ring belong to the phosphonium species E.  The reported HMBC experiment was done using the following pulse program: Avance-version (12/01/11); HMBC; 2D H-1/X correlation via heteronuclear zero and double quantum; coherence; optimized on long range couplings; no decoupling range acquisition; using gradient pulses for selection.